Method for manufacturing of drug-releasing stent coated with titanium-oxide thin film

ABSTRACT

Disclosed is a method for manufacturing a drug-releasing stent, including: coating a titanium dioxide or nitrogen-doped titanium dioxide thin film on a metal stent; and attaching a drug on the surface of the titanium oxide thin film. More specifically, the method for manufacturing a drug-releasing stent includes: coating a titanium dioxide or nitrogen-doped titanium dioxide thin film on a metal stent, which can be inserted into the blood vessel, by plasma enhanced chemical vapor deposition (PECVD); modifying the surface of the titanium oxide thin film with hydroxyl groups by low-temperature plasma; and chemically attaching a drug such as an antithrombotic drug or a neointimal hyperplasia inhibitor, so that the drug may be released in the blood vessel in a sustained manner.

CROSS-REFERENCE(S) TO RELATED APPLICATIONS

The present invention claims priority of Korean Patent Application No.10-2009-0062571, filed on Jul. 9, 2009, which is incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a drug-releasing stent which isinserted into a narrowed blood vessel to dilate the blood vessel andslowly releases a drug in the blood vessel, which is manufactured bycoating the surface of the stent with titanium oxide, modifying thesurface of the coated film, and chemically attaching the drug thereto.

2. Description of Related Art

A stent is a medical device inserted into a blood vessel narrowed due tovarious diseases to dilate the blood vessel and improve bloodcirculation. In general, the stent is inserted in heart blood vessels,aorta or brain blood vessels along with a balloon catheter, and theballoon is inflated to expand the coronary passage. As the ballooninflates, the stent expands outward and restores the blood vesselpassage to its original state. Accordingly, the existing stent requireselasticity and ductility. That is to say, the stent requires ductilitybecause it has to be inserted into complex and twisted passages.Further, upon insertion, elasticity is required to prevent deformationof the stent structure by the force applied from blood vessel tissues.For these reasons, corrosion-resistant stainless steel has been used tomanufacture the stent. Although the introduction of metal-based stentsavoids acute vessel closure and reduces restenosis after balloonangioplasty, restenosis in the stent resulting from neointimalhyperplasia during the restoration of the damaged blood vessel isbecoming a problem. As an effort to prevent the restenosis, a drug isprovided in the stent, so that the drug is supplied into the bloodvessel after the insertion of the stent. This drug therapy inhibits cellproliferation and, thereby, suppresses neointimal hyperplasia.

Meanwhile, recently, a technique of coating an aluminum thin film on thesurface of a stainless steel stent, oxidizing the aluminum film to forma nanostructure having multiple pores, and injecting a drug into thepores in order to prevent restenosis in the blood vessel was disclosedin Korean Patent Publication No. 10-2004-0011463.

Since the stent inserted in the blood vessel is in direct contact withthe blood vessel tissues, the surface of the stent should not be harmfulto the human body. Further, a special technique is required to injectthe drug into the stent.

Drug-releasing stents with organic compounds coated on the surface anddrugs attached thereto are disclosed in Korean Patent Application No.10-2005-0004331, Korean Patent Publication No. 10-2003-0020476 andothers. However, the safety of the organic compound coated film has notbeen confirmed yet in terms of blood compatibility, cytotoxicity, or thelike. In contrast, titanium oxide is biologically and biochemically safeand is widely used for cosmetics, food additives, or the like.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a method formanufacturing a drug-releasing stent capable of expanding a narrowedblood vessel, releasing a drug in a sustained manner and remainingstable for a long time in the body without cytotoxicity.

To attain the object, the present invention provides a method formanufacturing a drug-releasing stent comprising: a titanium oxide layercoated with TiO₂ or TiO_(2-x)N_(x) (wherein x is from 0.001 to 1) on ametal stent; and a drug coated layer with a drug attached on thetitanium oxide layer.

More specifically, the present invention provides a method formanufacturing a drug-releasing stent, comprising: forming a titaniumoxide [TiO₂ or TiO_(2-x)N_(x) (wherein x is from 0.001 to 1)] thin filmon the surface of a metal stent by plasma enhanced chemical vapordeposition (PECVD), modifying the thin film with a hydroxyl-substitutedsurface by a low-temperature plasma technique, and chemically attachinga drug thereto.

Thus manufactured drug-releasing stent remains stable for a long time inthe blood vessel without cytotoxicity, provides superior bloodcompatibility, and releases a drug into the bloodstream in a sustainedmanner.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically shows a plasma enhanced chemical vapor deposition(PECVD) apparatus for forming a titanium dioxide or nitrogen-dopedtitanium dioxide thin film.

FIG. 2 schematically shows a procedure of manufacturing an α-lipoic acidcoated stent.

FIG. 3 shows atomic force microscopys (AFMs) of the surface coated withtitanium dioxide or nitrogen-doped titanium dioxide.

FIG. 4 shows an electron spectroscopy for chemical analysis (ESCA)spectrum of a TiO₂ thin film deposited under the condition of 5 W, 4 hand 400° C.

FIG. 5 shows an ESCA spectrum of a nitrogen-doped TiO₂ thin filmdeposited under the condition of 5 W, 4 h and 400° C.

FIG. 6 shows the change of contact angle depending on the dischargepower applied for modification.

FIG. 7 shows the quantity of attached α-lipoic acid depending on thedischarge power applied for modification.

FIG. 8 shows attenuated total reflectance (ATR) Fourier transforminfrared spectroscopy (FT-IR) spectra after attachment of α-lipoic aciddepending on the discharge power applied for modification.

FIG. 9 shows an ESCA spectrum of an α-lipoic acid attached titaniumdioxide surface.

FIG. 10 shows scanning electron micrographs (SEMs) of an α-lipoic acidattached stent.

FIG. 11 shows SEMs of an α-lipoic acid attached stent after ultrasoniccleaning for 30 minutes.

FIG. 12 shows a drug release profile of a ReoPro-α-lipoic acid attachedstent.

DESCRIPTION OF SPECIFIC EMBODIMENTS

Hereinafter, the present invention will be described in more detail.

Prior to manufacturing a drug-releasing stent according to the presentinvention, a metal stent suitable to expand a narrowed blood vesselneeds to be selected. The metal stent of the present invention may beany known metal stent, without regard to type, length, weight, or thelike. Preferred is one having such an excellent elasticity that it doesnot experience change in shape while remaining for a long time in theblood vessel in spite of the pressure inside the blood vessel or otherenvironmental factors. Also preferred is one made of a non-corrosive andunharmful material. For example, the stents disclosed in Korean PatentPublication No. 10-2000-0069536, Korean Patent Publication No.10-1999-0035927, Korean Patent Publication No. 10-1999-0087472, KoreanPatent Publication No. 10-2002-0093610, Korean Patent Publication No.10-2004-0055785, or the like may be used. Preferably, the metal stent isbe made of a biocompatible metal material such as stainless steel,nitinol, tantalum, platinum, titanium, cobalt, chromium, cobalt-chromiumalloy, cobalt-chromium-molybdenum alloy, etc. Further, other knownbiocompatible metal materials or composites with biocompatible metalmaterials may be used.

With regard to the method for manufacturing a drug-releasing stent ofthe present invention, the following description will be made withrespect to a single metal stent unit, which refers to a single metalstent.

In the present invention, titanium oxide is deposited on the surface ofthe metal stent by means of plasma enhanced chemical vapor deposition(PECVD) of a titanium precursor.

In the present invention, PECVD may be performed using a commonly knownPECVD apparatus. For example, the PECVD apparatuses disclosed in KoreanPatent Application No. 10-2005-0058926, Korean Patent Application No.10-2001-0007030, Korean Patent Application No. 10-1990-0013643, or thelike may be employed. Preferably, as illustrated in FIG. 1, a PECVDapparatus equipped with a titanium wire G for fixing a stent in a plasmachamber, a decompression pump B connected to the plasma chamber, and abubbler C containing a titanium precursor and connected to gas tanks D,E, F so as to supply a vapor of the precursor into the plasma chamberalong with other gases may be used.

The present invention provides a method for manufacturing adrug-releasing stent, comprising:

(a) providing a titanium precursor, a carrier gas and a reactant gas ina plasma vacuum chamber and generating a plasma for 1 to 6 hours to forma titanium oxide thin film on the surface of a stent;

(b) providing steam or providing oxygen and hydrogen in the plasmavacuum chamber and generating a low-temperature plasma for 10 minutes to2 hours to modify the surface of the titanium oxide thin film; and

(c) reacting the titanium oxide thin film of the stent with a drug in anacidic solution and under an inert gas atmosphere at room temperature to100° C. for 30 minutes to 4 hours to attach the drug.

In the present invention, for the titanium precursor to deposit titaniumoxide on the metal stent, one or more selected from a group consistingof titanium butoxide, tetraethylmethylamino titanium, titanium ethoxide,titanium isopropoxide and tetramethylheptadiene titanium may be used.Besides, any known titanium precursor that provides superior depositionof titanium oxide on the metal stent by PECVD may be used.

In the present invention, prior to the deposition of titanium oxide onthe metal stent, the metal stent is fixed in the plasma vacuum chamberand the surface of the metal stent is pretreated by cleaning. Thepretreatment is performed to enhance deposition of the titanium oxidethin film on the stent, and is carried out by flowing a gas mixture ofargon and oxygen while maintaining the temperature in the plasma vacuumchamber at 200 to 600° C.

In the present invention, the titanium oxide deposited on the metalstent has two meanings. One is titanium dioxide (TiO₂) formed as oxygenis bound to titanium, and the other is nitrogen-doped titanium dioxide(TiO_(2-x)N_(x); x is from 0.001 to 1) formed as nitrogen is doped intotitanium dioxide. The titanium dioxide may have any crystal structureand may be in any form including rutile, anatase and brookite. The thinfilm of the two types of titanium oxide is formed on the surface of themetal stent by providing the carrier gas and the titanium precursor andgenerating a plasma while flowing the reactant gas. Either of the twotypes of titanium oxide is formed depending on the kind and flow rate ofthe reactant gas. For the carrier gas, one or more gas selected from agroup consisting of argon and helium may be flown along with thetitanium precursor, so that the carrier gas and the titanium precursorare introduced into the plasma chamber. Then, if a plasma is generatedby flowing oxygen only, titanium dioxide is deposited on the surface ofthe metal stent. And, if nitrogen is flown along with oxygen,nitrogen-doped titanium dioxide is deposited on the surface of the metalstent. Accordingly, it is preferred to select a nitrogen-free carriergas to deposit titanium dioxide (TiO₂) on the metal stent. As describedabove, titanium dioxide has proven biological and biochemical safety.And, nitrogen-doped titanium dioxide, which is obtained by dopingtitanium dioxide with nitrogen, is reported to have improvedantithrombotic effect by Kasrtari A et al. (Kastrati A, Mehilli J, PacheJ, Kaiser C, Valgimigli M, Kelbaek H, Menichelli M, Sabate M, Suttorp MJ, Baumgart D, Seyfarth M, Pfisterer M E, Schomig A. N. Engl. J. Med.,356, 1030, 2007.).

In the present invention, it is preferred that a bubbler is used tointroduce the titanium precursor into the plasma chamber in gas phase.The bubbler may be preheated at a temperature range adequate to vaporizethe titanium precursor, i.e. from room temperature to the boilingtemperature of the titanium precursor, and then the carrier gas may bepassed through the bubbler to be transferred to the plasma chamber. Atthis time, oxygen or oxygen and nitrogen may be transferred together toform titanium dioxide or nitrogen-doped titanium dioxide. After theintroduction of the titanium precursor, the carrier gas and the reactantgas into the plasma chamber, a plasma is generated in the plasma chamberto perform chemical deposition on the surface of the metal stent. Thecarrier gas may be flown at a rate of 50 to 500 sccm, preferably at 100to 200 sccm, and the reactant gas may be flown at a rate of about 10%that of the carrier gas, preferably at 10 to 100 sccm. In case thecarrier gas is a mixture of oxygen and nitrogen, the flow rate ofoxygen:nitrogen may be 1 to 9:9 to 1.

In the present invention, after the titanium precursor, the carrier gasand the reactant gas are provided in the plasma vacuum chamber, theplasma is generated to deposit titanium oxide on the surface of themetal stent. The discharge power of the plasma may be 1 to 300 W and thereaction may be performed for 1 to 6 hours, more preferably at 5 to 200W for 3 to 5 hours.

After the above procedure, the titanium oxide thin film formed on themetal stent may have a thickness of 10 to 500 nm, preferably 20 to 200nm.

In the present invention, the surface of the titanium oxide coated filmis modified by introducing hydroxyl (—OH) groups in order to attach thedrug on the titanium oxide coated film of the metal stent. The surfacemodification is performed inside the plasma vacuum chamber wherein thetitanium oxide film has been formed. It may be performed by providingsteam (H₂O) or a gas mixture of hydrogen and oxygen instead of steaminto the plasma vacuum chamber from a supply tube connected to theplasma vacuum chamber under a vacuum of 1×10⁻³ to 1 torr, preferably1×10⁻² to 1×10⁻¹ torr. Preferably, the steam or the gas mixture ofhydrogen and oxygen is provided at a rate of 1 to 50 sccm based on theunit stent. After the steam or the gas mixture of hydrogen and oxygen isintroduced into the plasma chamber, a plasma is generated to modify thesurface oxygen of the titanium dioxide or nitrogen-doped titaniumdioxide film with hydroxyl groups, as illustrated in FIG. 2 a. Theplasma discharge power may be 1 to 300 W and the reaction time may be 10minutes to 2 hours.

The titanium oxide thin film coated on the surface of the metal stent ismodified with hydroxyl groups because the drugs used in the presentinvention have carboxyl, aldehyde or alcohol functional groups and thusmay be easily bound on the surface of the titanium oxide throughdehydration with the hydroxyl groups of the modified titanium oxide filmunder an acidic condition. Since the drugs having various functionalgroups are physically attached on the surface of the stent in severallayers, upon insertion into the blood vessel, the drug-releasing stentmay release the drug physically attached thereto in a sustained manner,while maintaining the inherent structures of the titanium oxide and thedrug.

In the present invention, the drug attached on the titanium oxide thinfilm coated on the metal stent may be a drug capable of inhibitingneointimal hyperplasia or blood clot formation. For example, it may beone or more drug (s) selected from a group consisting of an anticancerdrug, an anti-inflammatory drug, a smooth muscle cell growth inhibitorand an antithrombotic drug. Only one drug may be physically orchemically bound on the surface of the titanium oxide layer, so that itmay be released in the body. Alternatively, two or more different drugsmay be independently bound on the surface of the titanium oxide layer togive a multidrug-releasing stent that releases two or more drugs. Incase the drug is a mixture of two or more drugs, each of the drugs maybe individually dispersed and bound directly on the surface of thetitanium oxide coated film or two or more of the drugs may be physicallyor chemically bound to each other by electrostatic attractions, hydrogenbonds, etc. between the drugs and then bound on the titanium oxidecoated film (see FIG. 2 b). For example, if lipoic acid and ReoPro arebound on the titanium oxide thin film together, lipoic acid may provideanti-inflammatory effect and ReoPro may improve antithrombotic effect.

In the present invention, the drug that may be bound on the titaniumoxide thin film of the metal stent includes all the drugs that may bebound to the hydroxyl groups introduced on the surface of titanium oxidethrough the surface modification. Especially, a drug having one or morefunctional group(s) selected from carboxyl, aldehyde and alcoholfunctional groups is easily bound on the titanium oxide thin film of themetal stent. Therefore, in the present invention, the drug may be one ormore selected from an anticancer drug, an anti-inflammatory drug, asmooth muscle cell growth inhibitor and an antithrombotic drug havingone or more functional group(s) selected from carboxyl, aldehyde andhydroxyl groups.

Examples of the drugs include molsidomine, linsidomine, nitroglycerin,hydralazine, verapamil, diltiazem, nifedipine, nimodipine, captopril,enalapril, lisinopril, quinapril, losartan, candesartan, irbesartan,valsartan, dexamethasone, betamethasone, prednisone, corticosteroid,17β-estradiol, cyclosporine, mycophenolic acid, tranilast, meloxicam,celebrex, indometacin, diclofenac, ibuprofen, naproxen, reserpine,hirudin, hirulog, agatroban, sirolimus (rapamycin), rapamycinderivatives, paclitaxel, 7-hexanoyltaxol, cisplatin, vinblastine,mitoxantrone, combretastatin A4, topotecan, methotrexate, flavopiridol,actinomycin, ReoPro (abciximab), α-lipoic acid, heparin, warfarin,aspirin, abiprofen, prostacyclin, or the like. Preferably, one or moreselected from heparin, ReoPro (abciximab), α-lipoic acid, sirolimus(rapamycin), actinomycin, molsidomine, linsidomine and paclitaxel may beused.

In the method for manufacturing a drug-releasing stent according to thepresent invention, the procedure (c) is performed by adding the titaniumoxide coated film metal stent with the hydroxyl groups introduced to aseparate reactor, mixing it with the drug and stirring in an acidicsolution under an inert gas atmosphere, after further adding distilledwater or an organic solvent if necessary.

Preferably, the distilled water may be ultrapure distilled water such astriple distilled water. And, preferably, the organic solvent may also bean ultrapure organic solvent with a purity 99.999% or better whichhardly contains impurities. The acidic solution serves the role of acatalyst in the reaction of the titanium oxide layer coated metal stentwith the drug. Preferably, the acidic solution is selected from sulfuricacid, nitric acid and hydrochloric acid. Most preferably, sulfuric acidis used. Preferably, the acidic solution is used in an amount of 10 to100 μL based on the unit metal stent. For the inert gas, nitrogen,helium, argon, or the like may be used. Preferably, all inert gas usedin the manufacturing of a drug-releasing stent according to the presentinvention is ultrapure gas with a purity 99.999% or better.

The procedure (c) may be performed by stirring at room temperature to100° C. for 30 minutes to 4 hours, preferably at 50 to 70° C. for 1 to 2hours.

After the reaction is completed, the stent may be recovered and cleanedaccording to a cleaning method known in the art. Preferably, it may bewashed with an ultrapure alcohol solvent, washed several times withtriple distilled water, and then dried to prepare a drug-releasing stentfor insertion into the blood vessel.

The chemical composition of the surface of thus manufactureddrug-releasing stent may be analyzed by attenuated total reflectance(ATR) Fourier transform infrared spectroscopy (FT-IR) (FT/IR 430,Miracle, Jasco) and electron spectroscopy for chemical analysis (ESCA)(VG Multilab 2000, ThermoVG Scientific). The surface state may beanalyzed using a scanning electron microscope (SEM, S-4700, Hitachi).The roughness and coating state of the thin film may be examined byatomic force microscopys (AFM). Further, the introduction of functionalgroups on the surface of the titanium dioxide thin film may be confirmedby measuring contact angle of the thin film surface with water beforeand after the surface modification using a contact angle analyzer (G-1,Erma). The binding of the titanium dioxide thin film with the stent andthe integrity thereof may be examined by scanning electron microscopy(SEM) after treating the titanium dioxide coated stent for 30 minutesusing an ultrasonic cleaner. Drug release test may be performed asfollows. The stent is immersed in 1×PBS buffer and stirred in anincubator at 30 to 50° C., preferably 35 to 40° C., while changing thePBS buffer every day. Then, the amount of the drug released into the PBSbuffer is measured based on UV absorption.

In accordance with the present invention, a thin film layer of titaniumdioxide (TiO₂) or nitrogen-doped titanium dioxide (TiO_(2-x)N_(x); x isfrom 0.001 to 1), which are known to have superior antithrombotic effectand biocompatibility, is coated on a metal stent to attach a drug to themetal stent. Since the PECVD technique employed for the thin filmcoating is known to give an impurity-free, uniform and stable thin film,it is considered suitable to deposit a stable thin film on the surfaceof the stent. Further, since titanium dioxide is biologically andbiochemically safe, being widely used for cosmetics, food additives, orthe like, and inexpensive, it is suitable as a thin film material of thedrug-releasing stent. Especially, it is reported that nitrogen doping ofthe titanium dioxide thin film further enhances antithrombotic effect.When coating the titanium dioxide layer, a more uniform thin film isattained at a lower discharge power. Given the same discharge power, anitrogen-doped titanium dioxide thin film prepared using a mixture ofoxygen and nitrogen features a more uniform surface than an undopedtitanium dioxide thin film. The drug-releasing stent manufactured inaccordance with the present invention exhibits superior adhesion betweenthe drug bound thin film layer and the stent and features uniformsurface without tearing or digging. Accordingly, it is considered thatthe coated thin film may remain firm without being detached from thestent during sterilization for insertion into the blood vessel or by thebloodstream, and have superior blood compatibility. Further, if two ormore drugs, such as heparin and α-lipoic acid or ReoPro and α-lipoicacid, are attached on the modified surface of the stent, the shortcomingof a single-drug stent may be resolved and α-lipoic acid may be releasedover a long period of time in a sustained manner.

EXAMPLES

The examples and experiments will now be described. The followingexamples and experiments are for illustrative purposes only and notintended to limit the scope of this disclosure.

Example 1 Preparation of Titanium Dioxide and Nitrogen-Doped TitaniumOxide (TiO_(2-x)N_(x)) Thin Films

A stent was fixed in a vacuum chamber connected to a radio frequency(RF) plasma generator and a vacuum pump using a titanium wire, asillustrated in FIG. 1. The temperature inside the plasma chamber wasmaintained at 400° C. In order to improve adhesion between the stent anda thin film, the surface of the stent was cleaned by a plasmapretreatment process by flowing argon and oxygen, prior to the coatingof the thin film. After adding titanium isopropoxide in a bubbler, thetitanium isopropoxide was mixed with oxygen, a reactant gas, andintroduced into the reaction chamber using argon as a carrier gas, whilemaintaining the temperature of the bubbler at 50° C. Then, a plasma wasgenerated for 4 hours to coat a titanium dioxide thin film on thesurface of the stent. The carrier gas argon was supplied at a rate of100 sccm, and the reactant gas oxygen was supplied at a rate of 20 sccm.Various thin films were formed while varying discharge power from 5 to200 W. Nitrogen-doped titanium dioxide thin films were prepared in asimilar manner, while supplying argon at a rate of 100 sccm, oxygen at10 sccm, and nitrogen at 1 sccm.

Example 2 Modification of Titanium Oxide Thin Film with Hydroxyl Groups

In order to chemically attach a drug on the surface of the coatedtitanium dioxide, the titanium oxide should have functional groups thatcan chemically bind to the functional groups of the drug molecules.Accordingly, the surface of titanium dioxide was modified using alow-temperature plasma and distilled water (H₂O) in order to introducehydroxyl (—OH) groups thereon. The titanium dioxide coated stent wasfixed in a tubular low-temperature plasma reactor made of Pyrex. Afterfilling triple distilled water in a bubbler, steam was supplied into theplasma reactor at a rate of 10 sccm. The titanium dioxide thin film wasmodified for 10 minutes via a low-temperature plasma process whilevarying discharge power from 10 to 100 W. The result of surfacemodification was confirmed by measuring a contact angle.

Example 3 Manufacture of α-Lipoic Acid Attached Stent

A two-neck round flask connected to a reflux condenser was purged withnitrogen, and the surface-modified unit stent, α-lipoic acid (0.5 g),distilled water (5 mL) and strong sulfuric acid (20 μL) were addedthereto. The mixture was stirred for 1 hour under a nitrogen atmospherewhile maintaining the temperature at 55° C. Upon completion of thereaction, the stent was recovered, washed 3 times with ethanol, washed 3times with flowing triple distilled water, blown with air, and dried ina desiccator.

Example 4 Manufacture of α-Lipoic Acid-ReoPro Attached Stent

The surface-modified unit stent, α-lipoic acid (0.5 mL, 25 mg/mL,thioctic acid 600T, Viatris GmbH & Co. KG), ReoPro (2 mL, 5 mg/mL, EliLilly and Company, Indianapolis, Ind.), distilled water (10 mL) andstrong sulfuric acid (40 μl) were added to a reactor configured in thesame manner as Example 3. The mixture was stirred for 1 hour under anitrogen atmosphere while maintaining the temperature at 55° C. Uponcompletion of the reaction, the stent was washed and dried in the samemanner as Example 3.

Evaluation

In order to measure the quantity of α-lipoic acid and ReoPro attached tothe stent, standard solutions with four concentrations were prepared foreach drug. Absorbance was measured using a UV spectrometer (Shimadzu1601, Japan) at 330 nm for α-lipoic acid and at 278 nm for ReoPro. Thus,calibration curves were drawn for α-lipoic acid and ReoPro. Then, inorder to measure the quantity of the drugs attached to the stent, each500 μL of the reaction solution was taken before and after the reaction,which were diluted by mixing with triple distilled water (2.5 mL) andsubjected to absorbance measurement at 278 nm and 330 nm, respectively.The measurement result was compared with the calibration curves todetermine the quantity of α-lipoic acid and ReoPro attached to thestent.

(a) Analysis of Physical and Chemical Structure of Thin Film

The chemical composition of the surface of the modified and drugattached stent was analyzed by attenuated total reflectance (ATR)Fourier transform infrared spectroscopy (FT-IR) (FT/IR 430, Miracle,Jasco) and electron spectroscopy for chemical analysis (ESCA) (VGMultilab 2000, ThermoVG Scientific). The surface state was analyzed byscanning electron microscopy (SEM, S-4700, Hitachi). The roughness andcoating state of the thin film was examined by atomic force microscopy(AFM). Further, the introduction of functional groups on the surface ofthe titanium dioxide thin film was confirmed by measuring contact angleof the thin film surface with water before and after the surfacemodification using a contact angle analyzer (G-1, Erma). The binding ofthe titanium dioxide thin film with the stent and the integrity thereofwere examined by SEM after treating the titanium dioxide coated stentfor 30 minutes using an ultrasonic cleaner. Drug release test wasperformed as follows. The stent was immersed in 1×PBS buffer and stirredin an incubator at 37° C., while changing the PBS buffer every day.Then, the amount of the drug released into the PBS buffer was measuredbased on UV absorption.

(b) Analysis of Surface Characteristics of Titanium Dioxide andNitrogen-Doped Titanium Dioxide Coated Stents

The coating of the titanium dioxide thin film may be performed atvarious discharge powers from 5 to 200 W. In order to investigate theeffect of discharge power on surface roughness, experiments wereperformed at different discharge powers of 5, 10 and 15 W. The result isshown in FIG. 3. In the table inserted in FIG. 3, the root mean square(RMS) thickness values of the thin films prepared at 400° C. for 4 hoursat different discharge powers of 5, 10 and 15 W. Atomic forcemicroscopys (AFMs) are also shown in FIG. 3. As seen from FIG. 3, thenitrogen-doped titanium dioxide thin films showed better surfaceuniformity than the titanium dioxide thin films, and a more uniform thinfilm could be attained at lower discharge power. The blood compatibilityis affected by the roughness of thin film. It is known that less surfaceroughness results in better blood compatibility.

The film prepared at 5 W had the lowest surface roughness. Hence,surface modification of the titanium dioxide thin film was performed ata fixed a discharge power of 5 W, for 4 hours at 400° C. FIG. 4 shows anESCA spectrum of the titanium dioxide thin film deposited at 5 W. Ti⁴⁺peaks of TiO₂ were observed at 458.8 eV (2p3/2) and 464.7 eV (2p1/2),and an O1s peak corresponding to the Ti—O bonding of TiO₂ was observedat 530.4 eV. FIG. 5 shows an ESCA spectrum of the nitrogen-dopedtitanium dioxide thin film. Ti and O1s peaks were observed at positionssimilar to those of the titanium dioxide thin film. Further, the N ispeak at 399 eV with a content of 0.8% confirms that nitrogen was dopedinto the surface of titanium dioxide.

(c) Analysis of Surface Modification of Titanium Dioxide Thin Films atDifferent Discharge Powers

After the surface modification of the titanium dioxide thin film usingH₂O in order to introduce hydroxyl groups, contact angle was measuredafter washing the surface once with distilled water. The relationshipbetween the contact angle and the discharge power applied for themodification is shown in FIG. 6. On the whole, the contact angle wassmaller than 40°, which indicates that hydrophilic functional groupswere introduced on the surface. The contact angle was lower at adischarge power range of 20 to 50 W, and the contact angle increased ata discharge power of 60 W or above. It may be because the titaniumdioxide thin film was partly etched or the structure of titanium dioxidewas changed at the high discharge power.

After binding a drug on the surface of the stent that had been modifiedwith hydroxyl groups, the amount of the bound drug was calculated usingthe calibration curves. FIG. 7 shows the quantity of attached α-lipoicacid depending on the discharge power. As seen from FIG. 7, the attachedamount was largest at 250 μg when the discharge power applied for thesurface modification was 20 W. The thin films modified at 10, 30, 40 and50 W showed attached amounts of about 150 μg. In contrast, the attachedamount decreased remarkably at 60 W, which suggest that the surface oftitanium dioxide might have been deformed or etched by the plasma.Therefore, it can be seen that a 10 to 50 W is ideal for modification ofthe titanium dioxide thin film using water.

(d) Analysis of Chemical Structure and Physical Properties of DrugAttached Surface

Upon the modification of the coated titanium dioxide thin film at adischarge power of 10 to 60 W followed by the addition of the drug, thechemical composition analysis by ATR FT-IR revealed that the drug wasstably attached. As seen from FIG. 8, the carbonyl (C═O) peak of theester (—C(O)O—) group, which is formed as the carboxyl group of α-lipoicacid binds with the hydroxyl (—OH) group of the titanium dioxidesurface, is found at 1710 cm⁻¹, at all discharge powers. FIG. 9 shows anESCA spectrum of an α-lipoic acid attached titanium dioxide surfacewhich had been deposited at 5 W and modified at 30 W using water. Thesurface chemical composition features S peaks, which result from theattachment of α-lipoic acid. Also, the high resolution ESCA of carbon ofthe spectrum shows the carbonyl peak of the ester group at 289 eV.

The surface state of the α-lipoic acid attached titanium dioxide wasobserved by SEM. The physical state of the stent surface is veryimportant because a torn or rough surface may result in easier bloodclot formation and quick restenosis. FIG. 10 shows scanning electronmicrographs (SEMs) of an α-lipoic acid attached stent which had beendeposited at 5 W and modified at 30 W using discharge water. It can beseen that the surface is very smooth with no tearing. The adhesionbetween the coated titanium dioxide thin film and the stent is importantsince a weak adhesion may result in easy detachment from the metalsurface. In order to evaluate the adhesion between the coated surfaceand the stent, the α-lipoic acid attached stent to soak in 1×PBS bufferwas treated using an ultrasonic cleaner for 30 minutes, after treatingusing an ultrasonic cleaner, the surface was observed by SEM. The resultis shown in FIG. 11. It can be seen that the stent remains stably asprior to the ultrasonic cleaning, without peeling or tearing. Therefore,it is considered that the coated thin film has a very uniform and smoothsurface and adheres well to the stent surface. FIG. 12 shows a drugrelease profile of a ReoPro-α-lipoic acid attached stent. As seen fromthe figure, ReoPro and α-lipoic were consistently released for 30 daysfrom the stent surface where the drugs were attached.

While the present invention has been described with respect to thespecific embodiments, it will be apparent to those skilled in the artthat various changes and modifications may be made without departingfrom the spirit and scope of the invention as defined in the followingclaims.

1. A drug-releasing stent comprising: a titanium oxide layer coated withTiO₂ or nitrogen-doped titanium oxide (TiO_(2-x)N_(x); x is from 0.001to 1) on a metal stent; and a drug coated layer with a drug attached onthe titanium oxide layer.
 2. The drug-releasing stent according to claim1, wherein the metal stent is made of a biocompatible metal selectedfrom a group consisting of chromium, cobalt and an alloy thereof.
 3. Thedrug-releasing stent according to claim 2, wherein the titanium oxidelayer has a thickness of 10 to 500 nm.
 4. The drug-releasing stentaccording to claim 3, wherein the drug is one or more selected from ananticancer drug, an anti-inflammatory drug, a smooth muscle cell growthinhibitor and an antithrombotic drug having one or more functionalgroups selected from carboxyl, aldehyde and hydroxyl groups.
 5. Thedrug-releasing stent according to claim 4, wherein one or more of thedrug is independently attached on the titanium oxide layer of thedrug-releasing stent.
 6. The drug-releasing stent according to claim 5,wherein the drug is one or more selected from heparin, ReoPro(abciximab), α-lipoic acid, sirolimus (rapamycin), actinomycin,molsidomine, linsidomine and paclitaxel.
 7. The drug-releasing stentaccording to claim 4, wherein two or more of the drug are attached onthe titanium oxide layer of the drug-releasing stent as bound chemicallyor physically to each other.
 8. The drug-releasing stent according toclaim 7, wherein the drug is one or more selected from heparin, ReoPro(abciximab), α-lipoic acid, sirolimus (rapamycin), actinomycin,molsidomine, linsidomine and paclitaxel.
 9. The drug-releasing stentaccording to claim 1, wherein the drug-releasing stent releases the drugin the body in a sustained manner.
 10. A method for manufacturing adrug-releasing stent, comprising: providing a titanium precursor, acarrier gas and a reactant gas in a plasma vacuum chamber and generatinga plasma for 1 to 6 hours to form a titanium oxide thin film on thesurface of a stent; providing steam or oxygen and hydrogen in the plasmavacuum chamber and generating a low-temperature plasma for 10 minutes to2 hours to modify the surface of the titanium oxide thin film; andreacting the titanium oxide thin film of the stent with a drug in anacidic solution and under an inert gas atmosphere at room temperature to100° C. for 30 minutes to 4 hours to attach the drug.
 11. The method formanufacturing a drug-releasing stent according to claim 10, wherein thetitanium precursor is one or more selected from a group consisting oftitanium butoxide, tetraethylmethylamino titanium, titanium ethoxide,titanium isopropoxide and tetramethylheptadiene titanium.
 12. The methodfor manufacturing a drug-releasing stent according to claim 10, whereinthe carrier gas is one or more selected from a group consisting of argonand helium.
 13. The method for manufacturing a drug-releasing stentaccording to claim 10, wherein the reactant gas is one or more selectedfrom a group consisting of steam, ozone and oxygen.
 14. The method formanufacturing a drug-releasing stent according to claim 13, whereinnitrogen gas is added to the reactant gas to form nitrogen-dopedtitanium oxide (TiO_(2-x)N_(x); x is from 0.001 to 1).
 15. The methodfor manufacturing a drug-releasing stent according to claim 10, whereinthe drug is one or more selected from a group consisting of heparin,ReoPro (abciximab), α-lipoic acid, sirolimus (rapamycin), actinomycin,molsidomine, linsidomine and paclitaxel.